Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Furoxans (1,2,5-oxadiazole-2-oxides) are widely used in organic chemistry as intermediate compounds for the synthesis of various heterocycles. Despite the fact that some furoxans have been found to possess remarkable biological activities, up to now no systematic study on their mode of action has been reported. The aim of the present study was to investigate the molecular mode of the vasodilator action of furoxans. Furoxans, but not the corresponding furazans, concentration-dependently increased coronary flow in an isolated working rat heart preparation. This effect was blunted upon coinfusion with methylene blue. All tested furoxans were demonstrated to increase potently the activity of soluble guanylate cyclase. Enzyme stimulation was found to be mediated by the generation of nitric oxide (NO) following chemical reaction of the furoxans with sulfhydryl groups of low molecular weight thiols and proteins. Furoxans are thus prodrugs which increase the level of cyclic GMP via formation of NO and may therefore be classified as nitrovasodilators. Along with the generation of NO, nitrite and nitrate ions and S-nitrosothiols were formed. The rates of formation of these metabolites, however, did not appear to be related to enzyme stimulation. A tentative reaction scheme that fits the obtained experimental data is proposed. Recently reported cytotoxic, mutagenic, immunosuppressive and anticancer effects of furoxans are discussed in the light of their ability to release NO upon reaction with thiols.
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PMID:Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans. 135 72

The effects of NG-nitro-L-arginine (NNA; an inhibitor of the oxidative L-arginine pathway) on convulsions induced by cyanide were investigated in mice. NNA prevented cyanide-induced convulsions in a dose-dependent manner. Furthermore, the inhibitory effect against convulsions induced by cyanide with NNA was abolished by pretreatment of L-arginine. However, NNA did not change blood cyanide levels in mice 5 min after injection of potassium cyanide. Since NNA prevents against oxidative L-arginine pathway-dependent guanylate cyclase activation in intact cells, it was suggested that the protection against cyanide-induced convulsions with NNA may be due to the inhibition of guanylate cyclase. In support, methylene blue, an inhibitor of guanylate cyclase, elicited a similar inhibition against convulsions induced by cyanide.
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PMID:Protective effect of NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) against cyanide-induced convulsions in mice. 173 19

Rats were injected sc with 120 micrograms/kg Soman, 120 micrograms/kg Sarin or 240 micrograms/kg Tabun. At 15 min, 2 h, or 6 h after administration, animals were decapitated along with saline-treated controls, and striatal activities of nucleotide cyclases and phosphodiesterases and striatal cyclic nucleotide levels were determined. All three agents had two similar effects on rat striatal cyclic nucleotide systems: they all increased cyclic GMP levels 15 min after their administration, and they all decreased guanylate cyclase activity 2 h after administration. There were also some different effects elicited by these three organophosphorus compounds. Different effects of Soman and Sarin seem to be mainly due to their different potencies, which in turn influence the time course of their actions. Tabun is quite different from Soman and Sarin in several respects: it rarely causes convulsions at sub-lethal doses, it has no effects on striatal cyclic AMP levels, and it affects enzyme activities 6 h after its administration. These differences may be due to the presence of cyanide instead of fluoride in its structure: i.e., this may be responsible for the different effects of Tabun on striatal cyclic nucleotide systems, and perhaps other biochemical effects. These results also indicate that other neurotransmitter systems, in addition to the cholinergic system, may be involved in organophosphate-induced toxicity.
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PMID:Acute effects of Soman, Sarin, and Tabun on cyclic nucleotide metabolism in rat striatum. 287 91

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.
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PMID:A new experimental model of epilepsy based on the intraventricular injection of endothelin. 750 66

In the present study, we examine the involvement of the L-arginine-nitric oxide pathway in seizure activity termination. Convulsions were induced reproducibly by intracerebroventricular administration of N-methyl-D-aspartate to conscious mice. The duration of the seizure activity was increased by inhibition of the NO-pathway or by intracerebroventricular injection of methylene blue, an inhibitor of guanylate cyclase activity. This increased duration in seizure activity was reversed by co-administration of L-arginine or by intracerebroventricular injection of guanosine 3':5' cyclic monophosphate (cGMP). These results suggest that nitric oxide produced in response to NMDA receptor activation leads to an increase in cGMP which induces the seizure activity termination.
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PMID:Nitric oxide: an endogenous anticonvulsant substance. 768 18

A solution containing S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO.-releasing compound, was microinjected in doses of 0.25-2 mumol into a lateral ventricle of conscious rats. SNAP produced dose-dependent convulsions similar to those associated with limbic stimulation, such as tonic extension of the hindlimbs and tail, and dystonia of the forepaws. At 2 mumol, SNAP evoked hyperventilation (arterial hypocapnia), arterial hyperglycemia and caused necrotic lesions of periventricular gray (e.g. lateral septal nucleus) and white matter structures. In the caudate nucleus and lateral septal nucleus ipsilateral to injection, SNAP elicited a bipolar metabolic pattern of low glucose metabolism proximal to the ventricle with higher values occurring more distally. In control studies, we proved that the residue of SNAP decomposition, N-acetylpenicillamine disulfide injected intraventricularly (2 mumol), was without physiological, behavioral, or histological effects. Ventricular pretreatment with methylene blue (2 nmol), a putative inhibitor of guanylate cyclase and superoxide generator, suppressed several of the behavioral manifestations of 1 mumol SNAP, such as the forepaw dystonia, squinting, and facial clonus, but was ineffective on the physiological and histological variables affected by the 2 mumol SNAP dose. Another NO. donor, sodium nitroprusside (2 mumol), produced fewer behavioral and cytotoxic effects over a 55-min observation period, but caused more intense and widely distributed metabolic stimulation, especially in commissural and projection white matter tracts. The results are the basis for a conscious rat model using intraventricular injection of nitrocompounds to examine the physiological, behavioral, metabolic and cytotoxic properties of NO. in the brain.
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PMID:Neurotoxicity in conscious rats following intraventricular SNAP, a nitric oxide donor. 796 12

In order to provide further support for a role of central nitric oxide as a mediator of penile erection and yawning, the nitric oxide donors sodium nitroprusside, hydroxylamine, isoamyl nitrite and S-nitroso-N-acetyl-penicillamine were injected into the lateral ventricles (i.c.v.) or into the paraventricular nucleus of the hypothalamus of male rats. Of the above compounds injected i.c.v., only isoamyl nitrite (10-100 micrograms) induced penile erection and yawning, while the others induced dramatic behavioral changes, such as motor hyperactivity and convulsions, that masked the above responses. Nevertheless, nitric oxide donors in doses ranging from 10 to 50 micrograms, for except S-nitroso-N-acetyl-penicillamine that was injected only at the dose of 10 micrograms and isoamyl nitrite that was not injected at all because of poor solubility, induced penile erection and yawning when injected in the paraventricular nucleus. Nitric oxide donor-induced responses were prevented by methylene blue and LY 83583, inhibitors of guanylate cyclase, the best known target of nitric oxide, given i.c.v. but not in the paraventricular nucleus. However, 8-bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a stable cGMP analog, and hemoglobin, a nitric oxide scavenger, were ineffective in inducing and preventing, respectively, penile erection and yawning when injected either i.c.v. or in the paraventricular nucleus. Nitric oxide donor-induced responses were also prevented by the nonapeptide oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin given i.c.v. but not in the paraventricular nucleus. The present results suggest that nitric oxide donors induce penile erection and yawning by activating central oxytocinergic transmission in the paraventricular nucleus of the hypothalamus via a cGMP-independent mechanism.
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PMID:Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. 878 10

ANP increases insulin levels in vivo. Because in vitro an ANP-induced increase in cGMP levels of islets of Langerhans was observed but no simultaneous increase in insulin release, secreted glucagon may be a candidate for this second messenger affected by ANP. The inhibitory effect of glucose on glucagon secretion was pronounced by 1.0 nM ANP at 3.0 mM glucose as well as at 5.6 and 8.3 mM glucose. Because in other tissues cGMP (the specific second messenger of ANP1 inhibits Ca2+ channels, the uptake of 45Ca2+ was investigated. ANP (1.0 nM) inhibited 45Ca2+ uptake, which was nearly completely abolished by a pertussis toxin (PT) pretreatment. The inhibition of 45Ca2+ uptake fits to inhibitory ANP effects on glucagon secretion but does not fit to insulin secretion. The glucagon secretion coupling cascade affected by ANP probably involves an increase in cGMP because 8-Br-cGMP (a membrane-permeable cGMP analogue) also decreased glucagon secretion. ANP(4-23), a truncated form of ANP, which is selective for the ANP clearance receptor, also inhibited glucagon secretion. HS-42-1, a guanylate cyclase receptor antagonist, tended to reverse the effect of ANP on glucagon release. The data indicate that in the presence of ANP, the in vivo homeostasis of glucose, though plasma insulin levels are increased, is not due to an ANP-mediated increase in glucagon secretion; ANP has a complex inhibitory effect on glucagon release. The data further indicate that the ANP-induced inhibition of glucagon secretion probably involves the cGMP system, an inhibition of Ca2+ uptake and the involvement of PT-sensitive G-proteins. Moreover, an involvement of the clearance receptor seems to be likely. ANP is a valuable tool for investigating glucagon secretion from pancreatic islets because paracrine effects of insulin can be excluded.
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PMID:Atrial natriuretic peptide (ANP)-induced inhibition of glucagon secretion: mechanism of action in isolated rat pancreatic islets. 889 23

Recent work has demonstrated that the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO). There is growing evidence that these gaseous molecules function as novel neural messengers in the brain. This article reviews the pertinent literature concerning the putative role of NO and CO as critical neurotransmitters and biological mediators of the neuroendocrine axis. Abundant evidence is presented which suggests that NO has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus. NO potently stimulates GnRH secretion and also appears to mediate the action of one of the major transmitters controlling GnRH secretion, glutamate. Evidence is presented which suggests that NO stimulates GnRH release due to its ability to modulate the heme-containing enzyme, guanylate cyclase, which leads to enhanced production of the second messenger molecule, cGMP. A physiological role for NO in the preovulatory LH surge was also evidenced by findings that inhibitors and antisense oligonucleotides to nitric oxide synthase (NOS) attenuate the steroid-induced and preovulatory LH surge. CO may also play a role in stimulating GnRH secretion as heme molecules stimulate GnRH release in vitro, an effect which requires heme oxygenase activity and is blocked by the gaseous scavenger molecule, hemoglobin. Evidence is also reviewed which suggests that NO acts to restrain the hypothalamic-pituitary-adrenal (HPA) axis, as it inhibits HPA stimulation by various stimulants such as interleukin-1 beta, vasopressin, and inflammation. This effect fits a proinflammatory role of NO as it leads to suppression of the release of the anti-inflammatory corticosteroids from the adrenal. Although not as intensely studied as NO, CO has been shown to suppress stimulated CRH release and may also function to restrain the HPA axis. Evidence implicating NO in the control of prolactin and growth hormone secretion is also reviewed and discussed, as is the possible role of NO acting directly at the anterior pituitary. Taken as a whole, the current data suggest that the diffusible gases, NO and CO, act as novel transmitters in the neuroendocrine axis and mediate a variety of important neuroendocrine functions.
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PMID:Gaseous transmitters and neuroendocrine regulation. 920

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.
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PMID:In vivo microdialysis study of GABA(A) and GABA(B) receptors modulating the glutamate receptor/NO/cyclic GMP pathway in the rat hippocampus. 942 28


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